title: The tumour-associated glycoprotein podoplanin is expressed in fibroblast-like synoviocytes of the hyperplastic synovial lining layer in rheumatoid arthritis.
abstract: BACKGROUND
  Activated fibroblast-like synoviocytes (FLSs) in rheumatoid arthritis (RA) share many characteristics with tumour cells and are key mediators of synovial tissue transformation and joint destruction. The glycoprotein podoplanin is upregulated in the invasive front of several human cancers and has been associated with epithelial-mesenchymal transition, increased cell migration and tissue invasion. The aim of this study was to investigate whether podoplanin is expressed in areas of synovial transformation in RA and especially in promigratory RA-FLS.
  
  
  METHODS
  Podoplanin expression in human synovial tissue from 18 RA patients and nine osteoarthritis (OA) patients was assessed by immunohistochemistry and confirmed by Western blot analysis. The expression was related to markers of synoviocytes and myofibroblasts detected by using confocal immunofluoresence microscopy. Expression of podoplanin, with or without the addition of proinflammatory cytokines and growth factors, in primary human FLS was evaluated by using flow cytometry.
  
  
  RESULTS
  Podoplanin was highly expressed in cadherin-11-positive cells throughout the synovial lining layer in RA. The expression was most pronounced in areas with lining layer hyperplasia and high matrix metalloproteinase 9 expression, where it coincided with upregulation of α-smooth muscle actin (α-sma). The synovium in OA was predominantly podoplanin-negative. Podoplanin was expressed in 50% of cultured primary FLSs, and the expression was increased by interleukin 1β, tumour necrosis factor α and transforming growth factor β receptor 1.
  
  
  CONCLUSIONS
  Here we show that podoplanin is highly expressed in FLSs of the invading synovial tissue in RA. The concomitant upregulation of α-sma and podoplanin in a subpopulation of FLSs indicates a myofibroblast phenotype. Proinflammatory mediators increased the podoplanin expression in cultured RA-FLS. We conclude that podoplanin might be involved in the synovial tissue transformation and increased migratory potential of activated FLSs in RA.
authors.affiliation: Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, Göteborg University, Box 480, 405 30 Göteborg, Sweden. anna-karin.hultgard.ekwall@rheuma.gu.se
authors.forename: Anna-Karin H
authors.initials: AK
authors.lastname: Ekwall
authors.forename: Thomas
authors.initials: T
authors.lastname: Eisler
authors.forename: Christian
authors.initials: C
authors.lastname: Anderberg
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Jin
authors.forename: Niclas
authors.initials: N
authors.lastname: Karlsson
authors.forename: Mikael
authors.initials: M
authors.lastname: Brisslert
authors.forename: Maria I
authors.initials: MI
authors.lastname: Bokarewa
mesh_terms: D000368:Aged; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D015153:Blotting, Western; D002469:Cell Separation; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D006965:Hyperplasia; D007150:Immunohistochemistry; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D018613:Microscopy, Confocal; D008875:Middle Aged; D013583:Synovial Membrane / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D000098853:Podoplanin
chemical_list: D008562:Membrane Glycoproteins; C117468:PDPN protein, human; D000098853:Podoplanin